Molecules that fight infection also work on the brain, causing anxiety or social interaction

Immune molecules called cytokines play an important role in the body’s defense against infections, helping to control inflammation and coordinate the responses of other immune cells. There is growing evidence that some of these molecules can also affect the brain, leading to behavioral changes during the disease.

Two new studies from MIT and Harvard Medical School, which highlight a cytokine called IL-17, now adds evidence. The researchers found that IL-17 acts on two different brain regions – the amygdala and the somatosensory cortex – plays two different roles. In the amygdala, IL-17 can cause anxiety, while in the cortex, it promotes social behavior.

Gloria Choi, associate professor of brain and cognitive science, said the findings show that the immune system and nervous system are closely linked, a member of the MIT’s Picower Institute for Learning and Memory and one of the senior authors of the study.

“If you get sick, there’s more to happen in your internal state, mood and behavioral state, and it’s not just about fatigue on your body. It’s about the brain,” she said.

Jun Huh, associate professor of immunology at Harvard Medical School, is also a senior author of two studies, appeared today at cell. One of the papers was led by Byeongjun Lee, a research scientist at the Kovo Institute and Jeong-tae Kwon, a former Picoll Institute research scientist, and the other was led by postdoctoral Yunjin Lee and Picower Institute Postdoc Tomoe Ishikawa, a postdoctoral fellow at Harvard Medical School.

Behavioral impact

Choi and Huh were interested in IL-17 a few years ago when they discovered it was involved in a phenomenon called the fever effect. Large-scale studies of children with autism have found that for many people, their behavioral symptoms temporarily weaken when they have a fever.

In a 2019 study of mice, Choi and Huh showed that in certain infections, IL-17 released and inhibited a small portion of the cerebral cortex, called S1DZ. Overactivation of neurons in this area can lead to symptoms of autistic behavior, including repetitive behavior and social reduction in mice.

“The molecule becomes the link between immune system activation (acting as fever) and changes in brain function and animal behavior,” Choi said.

IL-17 comes in six different forms, and there are five different receptors that can bind to it. In their two new papers, the researchers set out to map which of these receptors is expressed in different parts of the brain. This mapping suggests that a pair of receptors called IL-17RA and IL-17RB were found in the cortex, including the S1DZ region that the researchers had previously identified. This receptor is located in neurons that receive proprioceptive input and participate in controlling behavior.

When an IL-17, called IL-17E, binds to these receptors, neurons become less excited, leading to the behavioral effects seen in the 2019 study.

“IL-17E is necessary for behavior relief and does actually work like a neuromodulator because it will immediately reduce the excitability of these neurons,” Choi said. “So there is an immune molecule that acts as a neuromodulator in the brain, whose main function is to regulate the excitability of neurons.”

Choi hypothesized that IL-17 may have evolved initially as a neuromodulator and was later occupied by the immune system to play a role in promoting inflammation. This idea is consistent with previous work, suggesting that worms Career pole lineIL-17 has no effect in the immune system, but on neurons. In its effects in worms, IL-17 promotes the aggregation of a form of social behavior. Furthermore, in mammals, IL-17E is actually made from neurons in the cortex, including S1DZ.

“It is possible that the form of IL-17 that evolved first was a neuromodulator in the brain, and perhaps later hijacked by the immune system,” Choi said.

Cause anxiety

In another cell Paper, researchers explored another brain location and they discovered the IL-17 receptor-the amygdala. This almond-shaped structure plays an important role in dealing with emotions, including fear and anxiety.

The study showed that in a region called the basolateral amygdala (BLA), the working IL-17RA and IL-17RE receptors are expressed in discrete neurons. When these receptors bind to IL-17A and IL-17C, neurons become more excited, thereby increasing anxiety.

The researchers also found that counterintuitively, if the animals were treated with antibodies that block the IL-17 receptor, it would actually increase the amount of IL-17C that was circulating in the body. This finding may help explain unexpected results observed in clinical trials of drugs for psoriasis treatment for IL-17-RA receptors, especially regarding their potential adverse effects on mental health.

“We hypothesized that the IL-17 ligand that was upregulated in this patient cohort might act on the brain to induce suicidal awareness, and in animals, there is an anxious phenotype.”

During infection, this anxiety may be a beneficial response to keeping the patient away from others whose infection may be transmitted, Cui hypothesized.

“In addition to its main function of fighting pathogens, one of the ways the immune system works is to control host behavior, protect the host itself and protect the community to which the host belongs,” she said. “One of the methods of the immune system is to use cytokines, secreted factors, and use the brain as a communication tool.”

The researchers found that the same BLA neuron with the receptor of the IL-17 receptor also has the receptor for the IL-10 receptor, a cytokine that inhibits inflammation. The molecule counteracts the excitability produced by IL-17, making it stop anxiety once the body is useless.

Unique behavior

Together, the two studies show that the immune system, even a single cytokine series, can play various roles in the brain.

“Now, in two different brain regions, the combination of IL-17 receptors expressed in different neurons is different, and they regulate very different behaviors. One is actually somewhat positive and enhances social behavior, while the other is negative and the other is negative and causes anxiety phenotypes,” Choi said.

Her lab is now investigating other mappings of IL-17 receptor locations, as well as the IL-17 molecules bound to them, focusing on the S1DZ region. Ultimately, a better understanding of these neuroimmune interactions could help researchers develop new treatments for neurological diseases such as autism or depression.

“The fact that these molecules are made of the immune system has led us to take a novel approach to affecting brain function as a means of therapeutic therapy,” Choi said. “We can consider doing something with the immune system, rather than thinking about going straight to the brain?”

The research was funded, in part, by Jeongho Kim and the Brain Impact Foundation Neuro-Immune Fund, the Simons Foundation Autism Research Initiative, the Simons Center for the Social Brain, the Marcus Foundation, the N of One: Autism Research Foundation, the Burroughs Wellcome Fund, the Picower Institute Innovation Fund, the MIT John W. Jarve Seed Fund for Science Innovation, Young Soo Perry and Karen Ha, and the National Institute of Health.